Erlotinib 'dosing-to-rash': a phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer.

BACKGROUND: To evaluate the anticancer activity of erlotinib in patients with previously treated, advanced non-small cell lung cancer (NSCLC) whose dose is increased to that associated with a maximal level of tolerable skin toxicity (i.e., target rash (TR)); to characterise the pharmacokinetics (PK) and pharmacodynamics (PD) of higher doses of erlotinib. METHODS: Patients initially received erlotinib 150 mg per day. The dose was successively increased in each patient to that associated with a TR. Anticancer activity was evaluated. Plasma, skin, and hair were sampled for PK and PD studies. RESULTS: Erlotinib dose escalation to 200-475 mg per day was feasible in 38 (90%) of 42 patients. Twenty-four (57%) patients developed a TR, but 19 (79%) did so at 150 mg per day. Five (12%) patients, all of whom developed a TR, had a partial response. Median progression-free survival (PFS) was 2.3 months (95% CI: 1.61, 4.14); median PFS was 3.5 months and 1.9 months, respectively, for patients who did and did not experience a TR (hazard ratio, 0.51; P=0.051). Neither rash severity nor response correlated with erlotinib exposure. CONCLUSION: Intrapatient dose escalation of erlotinib does not appreciably increase the propensity to experience a maximal level of tolerable skin toxicity, or appear to increase the anticancer activity of erlotinib in NSCLC.

Increased TLR4 expression in murine placentas after oral infection with periodontal pathogens.

Maternal periodontitis has emerged as a putative risk factor for preterm births in humans. The periodontitis-associated dental biofilm is thought to serve as an important source of oral bacteria and related virulence factors that hematogenously disseminate and affect the fetoplacental unit; however the underlying biological mechanisms are yet to be fully elucidated. This study hypothesized that an oral infection with the human periodontal pathogens Campylobacter rectus and Porphyromonas gingivalis is able to induce fetal growth restriction, placental inflammation and enhance Toll-like receptors type 4 (TLR4) expression in a murine pregnancy model. Female Balb/C mice (n = 40) were orally infected with C. rectus and/or P. gingivalis over a 16-week period and mated once/week. Pregnant mice were sacrificed at embryonic day (E) 16.5 and placentas were collected and analyzed for TLR4 mRNA levels and qualitative protein expression by real-time PCR and immunofluorescence. TLR4 mRNA expression was found to be increased in the C. rectus-infected group (1.98 +/- 0.886-fold difference, P < 0.01, ANOVA) compared to controls. Microscopic analysis of murine placentas showed enhanced immunofluorescence of TLR4 in trophoblasts, mainly in the placental labyrinth layer. Also, combined oral infection with C. rectus and P. gingivalis significantly reduced the overall fecundity compared to controls (16.7% vs. 75%, infected vs. non-infected mice respectively, P = 0.03, Kaplan-Meier). The results supported an enhanced placental TLR4 expression after oral infection with periodontal pathogens. The TLR4 pathway has been implicated in the pathogenesis of preterm births; therefore the abnormal regulation of placental TLR4 may give new insights into how maternal periodontitis and periodontal pathogens might be linked to placental inflammation and preterm birth pathogenesis.

Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine.

PURPOSE: This phase II pilot study determined the efficacy and safety of alemtuzumab (Campath-1H; Burroughs Wellcome, United Kingdom) in patients with chronic lymphocytic leukemia (CLL), all of whom had previously received fludarabine and other chemotherapy regimens. PATIENTS AND METHODS: Twenty-four patients were treated with intravenous alemtuzumab at six centers in the United States. The target dose of 30 mg over 2 hours, three times weekly, was administered for up to 16 weeks. Responses were evaluated by an independent panel of experts using 1996 National Cancer Institute-sponsored Working Group criteria. Safety assessments included analysis of lymphocyte subpopulations. Antimicrobial prophylaxis was not mandatory. RESULTS: Eight patients (33%) achieved a major response (all partial remissions), with a median time to response of 3.9 months (range, 1.6 to 5.3 months). The median duration of response was 15.4 months (range, 4.6 to >or= 38.0 months), the median time to disease progression was 19.6 months (range, 7.7 to >or= 42.0 months), and the median survival time was 35.8 months (range, 8.8 to >or= 47.1 months). Acute infusion-related events, mainly grades 1 and 2, were most common and most severe in the first week. Ten patients (eight nonresponders and two responders) experienced major infections on-study. Pneumocystis carinii pneumonia was reported in two patients on-study; neither had received prophylaxis. Median CD4+ and CD8+ counts decreased and then began to increase by the end of the study, with further recovery by 1-month follow-up. One of 53 samples obtained from 10 patients had a low titer of alemtuzumab antibodies. CONCLUSION: Alemtuzumab has significant activity in poor-prognosis, fludarabine-treated CLL patients. However, because of a relatively high incidence of opportunistic infections accompanying profound lymphopenia, future protocols should include mandatory prophylaxis.

Natriuresis after cardiopulmonary bypass: relationship to urodilatin, atrial natriuretic factor, antidiuretic hormone, and aldosterone.

OBJECTIVE: Recent studies suggest that urodilatin from the kidneys rather than atrial natriuretic factor from the heart is the more important member of the family of natriuretic peptides involved in the normal regulation of renal sodium and water excretion. We thus examined the relationship between natriuresis, urodilatin, and atrial natriuretic factor in patients after cardiopulmonary bypass, a procedure known to increase levels of atrial natriuretic factor significantly. METHODS: Excretion rates of sodium and water were correlated with the excretion of urodilatin and with circulating levels of atrial natriuretic factor, antidiuretic hormone, aldosterone, and plasma renin activity during a period of 16 hours in 12 patients having had coronary artery bypass operations and with approximately a 400% elevation in levels of atrial natriuretic factor. RESULTS: Natriuresis did not correlate with atrial natriuretic factor, antidiuretic hormone, aldosterone, or plasma renin activity. Excretion rates of urodilatin, however, correlated significantly with excretion rates of sodium (r = 0.74, p = 0.03), urine flow (r = 0.83, p = 0.01), and with levels of serum sodium (r = 0.82, p = 0.01). CONCLUSION: These results suggest an important role for urodilatin, greater than that of atrial natriuretic factor, in the regulation of renal excretion of sodium and water after cardiopulmonary bypass surgery.

The U.S. health reform bill. "Good news and more questions".

PIP: The Clinton health care plan, known as the Health Security Act (HSA), includes coverage for reproductive health-related services such as family planning, prenatal care, and school-based health education. Of note, however, is the Act's careful avoidance of the word "sex" and ambiguity in terms of abortion and treatment for sexually transmitted diseases. The basic package provides coverage for approved contraceptive devices that are available by prescription. Contraceptive drugs, such as oral contraceptives, are presumably covered under benefits for prescription drugs. A comprehensive school health program, targeted at high-risk youth 10-19 years of age, will target the behaviors that result in unwanted pregnancies and sexually transmitted diseases. On the other hand, the HSA provides treatment only for "fertility-related infectious diseases," thereby excluding males and diseases such as syphilis that do not impact directly on fertility. Another concern is the HSA's Conscience Clause, which permits health professionals to opt out of delivering services that are in opposition to their religious beliefs. Provisions for confidentiality are not spelled out in the Act. Congressional debate around refinement of the HSA is expected to bring sexual health issues into the open.^ieng

Public policy update. Welfare reform and teen parents: are we missing the point?

PIP: The aim of teenage pregnancy prevention initiatives should be to provide sexuality education that is age-appropriate, medically accurate, and available at each grade level with a positive view of sexuality and information and skills that contribute to sexual health and the ability to make decisions. Abstinence should be included as long as it is not fear-based and is part of the promotion of responsible sexuality. Contraceptive information must be available to those already sexually active. Subsidized day care for children of poor adolescent mothers must be at the top of the agenda of services integrated with job programs and school-to-work initiatives. Quality child care can provide a solid foundation in personal health, negotiation, self-esteem, and individual rights and responsibilities. Quick-fix and punitive measures are out of place in programs that rely on growth in individual responsibility. An innovative approach to social welfare programming would include comprehensive sexuality education, reproductive health services, child care, health insurance, and job training. The Clinton welfare reform drafts combine elements of teen pregnancy prevention with punitive action. What is needed is greater investment in programs enhancing sexuality education, acceptance and understanding of sexuality, and access to affordable reproductive health services. The Clinton plan focuses primarily on the National Mobilization for Youth Opportunity and Responsibility, which is a national media campaign to educate youth about responsibility and the benefits of staying in school and delaying childbearing. About 1000 middle and high schools in high-poverty areas would be targeted. Opportunities would be offered to go to college or have access to job training. Controls would be placed on adolescents by requiring minor parents to live with a responsible adult, minor mothers to stay in school, and to limit disbursements for additional children while on Aid to Families with Dependent Children. Child support would be required of fathers. These key measures do not address the root causes of teen pregnancy. Teen pregnancy would decline if teenagers understood information on alternative to intercourse and sources and methods of contraception. Teenagers must be able to talk with partners about sexual limits and how to say "no" or avoid risky situations. Access to condoms or contraception must be available in the community at low or no cost.^ieng